Introduction
Polycystic ovarian syndrome (PCOS), also called Stein–Leventhal syndrome, is a heterogeneous endocrine disorder that affects approximately 4–8% of women of reproductive age. PCOS is characterized by anovulation, hyperandrogenism, menstrual irregularities, and insulin resistance. Signs and symptoms of women with this disorder include acne, hirsutism, obesity, infertility, oligomenorrhea or polymenorrhea which usually begin at the time of menarche (Box 93.1). The clinical hyperandrogenemia results from elevated ovarian production of testosterone and androstenedione, adrenal secretion of androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), increased skin 5α-reductase activity or a combination of these factors. Other common laboratory features of this syndrome include an elevated ratio of (>2) luteinizing hormone/follicle-stimulating hormone (LH/FSH) and decreased sex hormone-binding globulin (SHBG) levels. Testosterone levels are generally elevated but lower than levels seen with ovarian tumors and are typically less than 100–150 ng/dL.
Multiple metabolic sequelae are associated with PCOS and insulin resistance, especially when obesity is present, including increased risk of noninsulin-dependent diabetes mellitus, hyperlipidemia, hypertension, and cardiovascular disease. Other health risks include endometrial hyperplasia or even carcinoma and psychosocial dysfunction. Early recognition and diagnosis of this syndrome, appropriate screening for lipid abnormalities and diabetes, along with close follow-up and treatment are important for both short- and long-term health issues.
Definition and diagnostic criteria
In 1990, the National Institutes of Health defined PCOS as hyperandogenism and chronic anovulation where secondary causes such as hyperprolactinemia, adult-onset congenital adrenal hyperplasia or androgen-secreting neoplasm had been excluded. The presence of insulin resistance or polycystic-appearing ovaries was not included in the diagnostic criteria. Hyperandrogenism is established either by clinical findings such as hirsutism or acne or by elevated androgen levels.
Polycystic ovarian syndrome is a heterogeneous syndrome presenting with a wide variety of signs and symptoms (Box 93.2). The exact pathophysiology remains unknown and it is unlikely that any single factor will explain the entire spectrum.
Top-to-bottom theories imply a common central nervous system defect involving neurotransmitters such as dopamine, catecholamines, γ-aminobutyric acid (GABA), and endogenous opioids, and expressed by an imbalance of the LH/FSH ratio, enhanced LH pulsatility, and elevated bio-active LH.
Box 93.1 Criteria for the diagnosis of polycystic ovarian syndrome
- Clinical evidence of androgen excess: hirsutism, acne, androgenic alopecia, elevated total or free testosterone
- Oligo-ovulation since menarche: irregular cycles >35 or <24 days
- Exclusion of other disorders: nonclassic adrenal hyperplasia, androgen-secreting tumor, thyroid dysfunction, hyperprolactinemia
Presence of polycystic-appearing ovariesnot necessary for diagnosis
Box 93.2 Polycystic ovarian syndrome: important findings in history
- Menstrual history: lifetime history of irregular cycles, infertility
- Onset and progression of hirsutism, acne or alopecia: use of depilatory creams, dermatologic agents
- Change in bodyweight
- Medication use: use or abuse of anabolic or androgenic drugs; OCs or other medication, use and response
- Family history of endocrine disorders
The bottom-to-top theories describe either an ovarian-centered defect in the ovarian FSH receptor or a generalized impaired action of insulin on glucose transport and lipolysis. The insulin resistance of PCOS appears to be a postreceptor signaling aberration, different from the insulin resistance in simple obesity. Evidence strongly supports that insulin stimulates exaggerated production of androgens from ovarian theca cells, excessive growth of skin basal cells (resulting in acanthosis nigricans), abnormal peripheral and hepatic lipid metabolism leading to dyslipidemia, and decreased hepatic SHBG, resulting in higher levels of free androgens. The elevated androgen levels in the ovary inhibit the emergence of a dominant follicle and cause atresia of the follicle. Generalized insulin resistance occurs in up to 75% of all patients with PCOS, strongly suggesting a pathophysiologic role of hyperinsulinemia in the disorder.
Polycystic ovarian syndrome is associated with prolonged periods of anovulation and extraovarian estrogen production, largely through increased peripheral conversion of androstenedione to estrone coupled with elevated levels of unbound estradiol. Persistent acyclic estrogen in conjunction with an absence of luteal-phase progesterone causes prolonged stimulation to the endometrium and may lead to simple hyperplasia, complex hyperplasia, or endometrial carcinoma. Interestingly, women in the Nurses’ Health Study with the most irregular menstrual cycles were reported to have a reduced risk of breast cancer.
Androgen excess in PCOS is associated with hirsutism, acne, excess sebum production, android obesity, and androgenic alopecia (Box 93.3). The hyperandrogenism in PCOS is principally from ovarian overproduction, but the adrenal gland may contribute.
Most PCOS women have lipoprotein abnormalities, with low levels of high-density cholesterol and increased levels of low-density cholesterol and triglycerides. These findings, along with hyperinsulinemia, contribute to a substantial increased risk of cardiovascular disease, hypertension, and diabetes mellitus. Central android obesity is a predictor of cardiovascular disease and menstrual irregularities.
Box 93.3 Polycystic ovarian syndrome: critical parts of physical examination
Look for:
- excessive hair growth, location, thickness, pattern
- acne, alopecia, acanthosis nigricans
- obesity, fat distribution
- galactorrhea
Exclude:
- pelvic/abdominal masses
- virilization or masculinization (breast size, change)
- thyroid enlargement
- Cushingoid features (muscle weakness, central obesity, hypertension)
- signs of systemic illness
Classically, polycystic ovaries are defined as enlarged ovaries, often 1.5 to 3 times larger than normal, with 10 or more subcapsular follicles located in the periphery of the ovarian cortex which are 2–10 mm in diameter. These multiple follicles are typically arranged peripherally around an enlarged central mass of stromal tissue. Demonstration of stromal hypertrophy on ultrasound is reported in 80% of patients diagnosed with PCOS. The presence of polycystic-appearing ovaries on ultrasound or in surgery does not establish the diagnosis of PCOS, as high levels of circulating androgens from any source may cause the accumulation of small atretic follicles in the cortex. Other conditions that may demonstrate polycystic-appearing ovaries include Cushing’s syndrome, congenital adrenal hyperplasia, adrenal tumors, thyroid disorders, bulimia nervosa, obesity, women on oral contraceptives, and normal women. Generally, polycystic-appearing ovaries have an exaggerated response to ovulation induction agents and greater care must be used.
The major two criteria for the diagnosis of PCOS are hyperandrogenism and chronic anovulation. Hyperandrogenism may arise from either elevated serum androgens or clinical manifestations of hyperandrogenism such as acne or hirsutism. It is important to exclude other androgen disorders such as an ovarian tumor or adrenal hyperplasia. The clinical criteria of the polycystic ovarian syndrome are listed in Box 93.1.
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